The goal of this proposal is to extend genetic studies of congenital left ventricular outflow tract obstruction (LVOTO) defects through a genome wide association (GWA) study. Clinical embryology, epidemiology, and cytogenetic data provide strong support for the importance of genetic factors in this class of cardiovascular malformations (CVM). Formal inheritance analyses are most consistent with an oligogenic/complex genetic mechanism underlying most cases. New epidemiologic data has provided more precise estimates of heritability, first degree relative risk, as well as sex and ethnic differences in prevalence rate. The first and second Specific Aims of this proposal involve genotyping case-parent trios with a panel of >500,000 single nucleotide polymorphisms (SNPs, Affymetrix Genome-Wide Human SNP Array 5.0). We propose to use Family Based Association Tests (FBAT) statistics for association analyses of single markers and haplotypes. Our sample will be composed exclusively of at least 700 Caucasian caseparent trios. Because there is significant sex rate difference, we will stratify by sex in the primary analysis. We will also examine for maternal genotype and parent of origin effects. We will use Multidimensional Reduction (MDR) and candidate gene methods to examine for epistasis. We will also use hybridization intensity data to identify inherited copy number variants (CNVs) and de novo submicroscopic chromosomal aberrations, infer the CNV genotypes, and test for CNV-disease associations. The third Specific Aim will carry out more thorough linkage disequilibrium mapping on promising regions identified in the primary GWA screen. We will use positive false discovery rate methods to help prioritize loci. We will use multipoint and haplotype methods to verify association in case parent trios and to refine the location of the potentially causal variants. The fourth Specific Aim will assess the validity of potential positive associations through replication in a sample of 1000 cases and 2000 controls obtained from the Texas Department of Health Birth Defects Surveillance program. Identification of genes involved in congenital LVOTO defects should provide both new mechanistic insights and improve diagnostic testing in individual patients and families.